Association of preexisting psychiatric disorders with post-COVID-19 prevalence: a cross-sectional study

Evidence demonstrating the association of preexisting psychiatric disorders with post-COVID-19 is limited. We aim to investigate the association using larger sample sizes and more extended postinfection periods than previous studies. A total of 6015 (response rate = 77.5%) COVID-19 survivors were surveyed using a self-administered questionnaire from July to September 2021. Poisson regression analysis with robust error variance was performed to estimate post-COVID-19 prevalence ratios (PRs) with or without preexisting psychiatric disorders. Participants with preexisting psychiatric disorders numbered 1067 (17.7%), and with post-COVID-19 were 2149 (35.7%). Post-COVID-19 PR with preexisting psychiatric disorders was 1.09 (95% CI 1.02–1.18, p = 0.013). The interaction between preexisting psychiatric disorders and postinfection periods was significant (p for interaction < 0.001). The subgroup analysis showed that those with preexisting psychiatric disorders might be at greater prolonged risk of post-COVID-19 than those without the disorders. These findings suggested that preexisting psychiatric disorders were associated with an increased post-COVID-19 risk, and post-COVID-19 with preexisting psychiatric disorders might prolong even if time passes.


Scientific Reports
| (2023) 13:346 | https://doi.org/10.1038/s41598-023-27405-w www.nature.com/scientificreports/ However, previous studies that investigated the association of preexisting psychiatric disorders with post-COVID-19 had small sample sizes and short postinfection periods: the median interval from test to interview date was 16 days (the interquartile range was 14-19 days), and the median interval of symptom assessment was 10 weeks after the initial COVID-19 symptoms 9,10 . Therefore, the evidence about the association of preexisting psychiatric disorders with post-COVID-19 and the difference in the risk of a more extended postinfection period with or without preexisting psychiatric disorders are still limited. Moreover, a previous study showed that the rate of medication use among people with psychiatric symptoms was low in Japan 14 . The clinical data of medical settings would not be sufficient to determine the prevalence and the course of post-COVID-19. Therefore, confirming the association between preexisting psychiatric disorders and post-COVID-19 among people who would not have used medical care after recovering from COVID-19 infection is necessary. Our previous study showed that the courses of depressive and anxiety symptoms after the infection of COVID-19 were more severe in COVID-19 survivors with preexisting psychiatric disorders than in those without the disorders 15 . However, the association between preexisting psychiatric disorders and physical symptoms of post-COVID-19 is still unknown.
This study aims to investigate the association between preexisting psychiatric disorders and physical symptoms of post-COVID-19 and the interaction of preexisting psychiatric disorders and postinfection period on physical symptoms of post-COVID-19 in larger sample size and more extended postinfection period than those of previous studies by an internet survey.

Methods
Participants. Participants who have contracted the new coronavirus were surveyed using a web-based cross-section analysis from July to September 2021. The study sample was from the pooled panels of an internet research agency (Rakuten Insight, Inc.), which had approximately 2.2 million panelists in 2019. All participants provided web-based informed consent at registration. Only the participants who responded "yes" to the first question, "Have you ever been infected with COVID-19?" were asked to complete the questionnaire. We excluded participants who completed the questionnaire (n = 7760) who (1) incorrectly answered the dummy question (n = 1195); (2) disclosed not having been infected during the survey (n = 6); (3) gave inconsistent answers about physical symptoms (n = 454); (4) gave improbable answers about the postinfection period (not within 0-20 months) judging from the date of confirmed the first case of COVID-19 infection in Japan (January 15, 2020) 16 (n = 84); (5) answered in the open-ended section, which could not categorize existing choices of the questionnaire (n = 5); and (6) identified some fault in data (n = 1). The participant flow chart is shown in Fig. 1. www.nature.com/scientificreports/ Finally, 6015 individuals (response rate = 77.5%) were included in the analyses. The study was in accordance with the Declaration of Helsinki. All methods were performed in accordance with the relevant guidelines and regulations. The participation was anonymous. A credit point that could be used for internet shopping and cash conversion was provided for participants with an incentive. We used the term gender according to the SAGER guidelines 17 . This study was approved by the Ethical Board of the National Center of Neurology and Psychiatry in Japan (A2021-34).

Measurement. Outcome variables.
Post-COVID-19. Post-COVID-19 was dichotomized into "yes" and "no. " We identified post-COVID-19 based on the WHO definition 2 . We asked the question: "What symptoms do you have?" Participants could choose multiple answers from the options of symptoms based on the WHO definition of post-COVID-19. Responses were categorized as "yes" when participants chose any one of these considered physical symptoms (menstrual and period problems, altered smell, altered taste, blurred vision, chest pain, cough, dizziness, fatigue, [intermittent] fever, gastrointestinal issues [diarrhea, constipation, or acid reflux], headache, muscle pain or spasms or neuralgias, shortness of breath, tachycardia or palpitations, and tinnitus and other hearing issues). Post-COVID-19 that participants described in the open-ended section were reviewed by four researchers and allocated the type of symptoms they should be applied to.
Exposure variables. Preexisting psychiatric disorders. Preexisting psychiatric disorders were categorized by the answers to the question: "Have you ever been diagnosed with or experienced psychiatric problems before the COVID-19 pandemic?" Participants chose multiple answers from the following options of symptoms: "Nothing, " "Depressive disorder, " "Bipolar disorder, " "Panic attack or panic disorder, " "Anxiety disorder or anxietyrelated problems (e.g., hypersensitivity, worry, fear, obsessive-compulsive symptoms), " "Alcohol use disorder or alcohol abuse/dependence, " "The use of illicit substances or psychotropics without prescription, " "Burnout syndrome, " and "Others" (with an optional comment field). Preexisting psychiatric disorders were dichotomized into "yes" and "no" based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) 18 .
Those who chose any one of these disorders (depressive disorder, bipolar disorder, panic attack or panic disorder, anxiety disorder, or anxiety-related problems [e.g., hypersensitivity, worry, fear, and obsessive-compulsive symptoms]) were categorized into the group "yes" preexisting psychiatric disorders. Those who chose options only "Nothing, " "The use of illicit substances or psychotropics without prescription, " or "Burnout syndrome" were categorized into the group "no" preexisting psychiatric disorders. We considered that "The use of illicit substances or psychotropics without prescription" did not meet the diagnostic criteria for alcohol use disorder without the information on duration, amount of use, and symptoms. Moreover, the DSM-5 does not include Burnout syndrome. Among those who chose only "Others, " those whose comments in the comment field matched the DSM-5 diagnosis were categorized into the group "yes" preexisting psychiatric disorders.
Statistical analyses. The post-COVID-19 prevalence ratios (PRs) were estimated using Poisson regression analysis with a robust error variance. We used this model because the post-COVID-19 prevalence is over 10%, and the odds ratio could overestimate the PRs 25 . Variance inflation factor (VIF) was used to check for multicollinearity. Most of the VIF values were less than 2, and the mean VIF of the model was < 2. We entered K6 and work status as covariates because we considered that these were important covariates, although they were over 2 (K6: ≥ 13 = 2.18; work status: self-employed = 2.28 and permanent employment = 2.01). We also estimated the interaction between preexisting psychiatric disorders and postinfection periods. We then conducted a subgroup analysis by postinfection periods because the interaction between preexisting psychiatric disorders and postin-
Interaction between preexisting psychiatric disorders and postinfection periods. The interaction between preexisting psychiatric disorders and postinfection periods was significant (p for interaction < 0.001) ( Table 2). The subgroup analysis by postinfection period showed that PRs of with preexisting psychiatric disorders for reference (without preexisting psychiatric disorders) in each postinfection period were following (<  (Fig. 2).

Discussion
This study investigated the association between preexisting psychiatric disorders and post-COVID-19 and the interaction of preexisting psychiatric disorders and postinfection periods using a web-based cross-sectional survey. The results showed that preexisting psychiatric disorders were associated with a slight increase in PR of post-COVID-19. Preexisting psychiatric disorders might tend to be at greater prolonged risk of post-COVID-19 than those without preexisting psychiatric disorders, except for ≥ 1 to < 3 months. The result that preexisting psychiatric disorders were associated with an increase in PR of post-COVID-19 was consistent with previous cross-sectional studies about COVID-19 survivors that showed preexisting psychiatric disorders were associated with not returning to the patient's usual health or over-represented fatigue as post-COVID-19 9,10 . Previous studies suggested that current psychiatric disorders would cause physical symptoms 26,27 . However, the association of preexisting psychiatric disorders with post-COVID-19 was significant after adjustment for current depressive and anxiety symptoms in this study. It might be better to pay attention to the difference in the clinical course of post COVID-19 with or without preexisting psychiatric disorders. Previous metaanalyses showed that levels of inflammatory cytokines increased in patients with psychiatric disorders compared with controls 28,29 . Moreover, a previous study showed that the levels of inflammatory cytokines also increased in patients with post-COVID-19 30 . The overproduction of inflammatory cytokines could play an essential role in the cause and progress of various diseases 31 . The activation of the inflammatory response system caused by psychiatric disorders might be associated with higher PR among the participants with preexisting psychiatric disorders.
Preexisting psychiatric disorders might be at greater prolonged risk of post-COVID-19 than those without preexisting psychiatric disorders. The result could be consistent with previous studies that people with psychiatric disorders were associated with increased risks of chronic physical symptoms compared with those without psychiatric disorders 12,13 . There are some possible factors to prolong physical symptoms among people with psychiatric disorders. Previous studies, for example, suggested that current psychiatric symptoms 32 , the psychological factor of fear-avoidance 33,34 , and the neuropsychological factor of pain sensitivity 35 were associated with chronic physical symptoms. However, these associations are still unclear. Further study will be needed to investigate the mechanism of preexisting psychiatric disorders, post-COVID-19, and both biological and nonbiological factors.
Unexpectedly, only in the postinfection period was ≥ 1 to < 3 months, the trend of greater risk of post-COVID-19 with preexisting psychiatric disorders was not observed. A previous study suggested that the persistence of physical symptoms differed with the type of psychiatric disorder 36 . The course of physical symptoms of post-COVID-19 might differ depending on the type of preexisting psychiatric disorders. Further research is needed to determine the relationship between the type of preexisting psychiatric disorders and the severity and course of physical symptoms of post-COVID-19 to identify populations needing recovery support.

Limitations
This study had several limitations: first, this study was conducted using an internet survey. Participants were extracted from individuals who were registered as monitors of the research agency and agreed to call for research cooperation. Participants who were concerned with post-COVID-19, psychological distress, or psychiatric conditions would be more likely to respond to the survey, which could result in an overestimation of post-COVID-19 and psychiatric conditions. Therefore, the generalizability may be limited because of the possibility of sampling bias. Second, this study used self-administered questionnaires. There is a consistency limitation with the clinical definition of preexisting disorders and post-COVID-19. The limitation could also result in an overestimation of the prevalence of preexisting disorders and post-COVID-19 because of the same reason for sampling bias. Moreover, recall bias could occur if participants with post-COVID-19 had cognitive decline, which may be more common in those with preexisting psychiatric disorders. The limitation could also affect the results. Third, this study used a dichotomous variable about the presence of post-COVID- 19

Conclusions
Our analyses suggested that preexisting psychiatric disorders of COVID-19 survivors were associated with an increased the risk of physical symptoms of post-COVID-19. Moreover, preexisting psychiatric disorders might be at greater prolonged risk of post-COVID-19 than those without preexisting psychiatric disorders.

Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.